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A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer

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Abstract

Purpose

To evaluate whether adding humanized monoclonal insulin growth factor-1 receptor (IGF-1R) antibody (dalotuzumab) to mammalian target of rapamycin (mTOR) inhibitor (ridaforolimus) plus aromatase inhibitor (exemestane) improves outcomes in patients with estrogen receptor (ER)-positive advanced/metastatic breast cancer.

Methods

This randomized, open-label, phase II trial enrolled 80 postmenopausal women with high-proliferation (Ki67 index staining ≥15%), ER-positive breast cancer that progressed after a non-steroidal aromatase inhibitor (NCT01605396). Randomly assigned patients were given oral ridaforolimus 10 mg QD 5 ×/week, intravenous dalotuzumab 10 mg/kg/week, and oral exemestane 25 mg/day (R/D/E, n = 40), or ridaforolimus 30 mg QD 5 ×/week and exemestane 25 mg/day (R/E; n = 40). Primary end point was progression-free survival (PFS).

Results

Median PFS was 23.3 weeks for R/D/E versus 31.9 weeks for R/E (hazard ratio 1.18; 80% CI 0.81–1.72; P = 0.565). Grade 3–5 adverse events were reported in 67.5% of patients in the R/E arm and 59.0% in the R/D/E arm. Stomatitis (95.0 vs. 76.9%; P = 0.021) and pneumonitis (22.5 vs. 5.1%; P = 0.027) occurred more frequently in the R/E than the R/D/E arm; hyperglycemia (27.5 vs. 28.2%) occurred at a similar rate.

Conclusions

R/D/E did not improve PFS compared with R/E. Because the PFS reported for R/E was similar to that reported for everolimus plus exemestane in patients with advanced breast cancer, it is possible that lower-dose ridaforolimus in the R/D/E arm (from overlapping toxicities with IGF1R inhibitor) contributed to lack of improved PFS.

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Acknowledgements

We thank the patients and their families for their participation and support during the study as well as the study center staff and principal investigators. Editorial support was provided by Tim Ibbotson, PhD, of ApotheCom and was funded by Merck & Co., Inc., Kenilworth, NJ.

Funding

This work was supported by a grant from Merck & Co., Inc.

Author information

Author notes

  1. Andrew Denker

    Present address: Alexion Pharmaceuticals, New Haven, CT, USA

  2. Antoinette R. Tan

    Present address: Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC, USA

  3. Mary Beth Jones

    Present address: Checkmate Pharmaceuticals, Cambridge, MA, USA

Authors and Affiliations

  1. UCSF Helen, Diller Family Comprehensive Cancer Center, 1600 Divisadero Street, San Francisco, CA, 94115, USA

    Hope S. Rugo

  2. Centre Léon Bérard, Lyon, France

    Olivier Trédan

  3. National Cancer Center, Goyang, Republic of Korea

    Jungsil Ro

  4. H. de Lleida Arnau de Vilanova, Lerida, Spain

    Serafin M. Morales

  5. Institut de Cancérologie de l’Ouest, St Herblain-Nantes, France

    Mario Campone

  6. University Hospital of Parma, Parma, Italy

    Antonino Musolino

  7. Instituto Português de Oncologia Francisco Gentil, Porto, Portugal

    Noémia Afonso & Marta Ferreira

  8. Korea University Medical Center, Seoul, Republic of Korea

    Kyong Hwa Park

  9. Ramón y Cajal University Hospital, Madrid and Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Javier Cortes

  10. Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Antoinette R. Tan

  11. Baylor Sammons Cancer Center, Texas Oncology, US Oncology, Dallas, TX, USA

    Joanne L. Blum

  12. Merck& Co., Inc., Kenilworth, NJ, USA

    Lamar Eaton, Christine K. Gause, Zhen Wang, Ellie Im, David J. Mauro, Mary Beth Jones & Andrew Denker

  13. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    José Baselga

Authors
  1. Hope S. Rugo
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  20. José Baselga
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Corresponding author

Correspondence to Hope S. Rugo.

Ethics declarations

Conflicts of interest

JC has received fees for lectures and consulting from Roche, Celgene, Novartis, and Eisai. HSR has received research support from Merck & Co., Inc. and Novartis. ART received grants from Merck & Co., Inc. for conducting this study. AD, CKG, EI, MBJ, DJM, and ZW are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ and may hold stock or stock options in the company. MF has received grants from Merck Sharp & Dohme Corp. and AstraZeneca, grants and non-financial support from Novartis, and F. Hoffmann-La Roche, and non-financial support from Merck Sharp & Dohme Corp. NA, JB, JLB, MC, LE, AM, JR, SMM, OT, and KHP have nothing to disclose.

Ethical approval

The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Independent ethics committees reviewed and approved the protocol and applicable amendments for each institution.

Informed consent

Written informed consent was obtained from all participants.

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Rugo, H.S., Trédan, O., Ro, J. et al. A randomized phase II trial of ridaforolimus, dalotuzumab, and exemestane compared with ridaforolimus and exemestane in patients with advanced breast cancer. Breast Cancer Res Treat 165, 601–609 (2017). https://doi.org/10.1007/s10549-017-4375-5

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  • DOI: https://doi.org/10.1007/s10549-017-4375-5

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